An increase in the carbon dioxide concentration in arterial blood caused by disease or altered environment has a profound effect on breathing. It is thought that the brain stem chemoreceptors primarily responsible are stimulated by hydrogen ion changes which are determined by the reaction of CO2 with water in the tissue and by the activities of other strongly dissociated ions. This study is based on the hypothesis that carrier mediated transport of ions across cell membranes is a cardinal step in determining the stimulus to the respiratory chemoreceptors in the brain stem. We propose to evaluate this hypothesis by experiments in anesthetized cats and rabbits, measuring the ventilatory response to acute respiratory acidosis. Inhibitors of carrier mediated sodium/potassium coupled chloride exchange will be administered by perfusing the cerebrospinal fluid space of the brain stem via the cisterna magna. Precise localization of region and cell type for the inhibitors of ion exchange will be made by quantitative immunofluorescence microscopy. The effect of ion transport inhibition on extracellular fluid pH will be determined at the site of the chemoreceptors and the effect on intracellular elemental concentrations by electron probe microanalysis. The objective of this work is an understanding of the chemical processes responsible for the medullary chemoreceptors role in controlling breathing during acid-base disturbances which result from acute or chronic respiratory failure.